Why Might PET be a Good Surrogate Marker in AD?

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Presented by William Jagust, M.D. at
the November 18, 2002 Peripheral and Central
Nervous System Advisory Committee meeting
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Why is PET a Good Potential Surrogate Marker in
AD?

• PET is a good assay for tissue biochemistry and
  physiology that is related to disease process
• PET is highly related to cognitive function and
  predictive of cognitive decline
• PET is sensitive, reliable, and valid as a marker
  for AD pathology
• PET provides statistically powerful measures of
  decline

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PET Tracers Relevant to AD

• Radioligands that bind to acetylcholinesterase
• Reflect cholinergic function
• Radioligands that bind to amyloid
• Reflect unknown characteristics of amyloid
  pathology
• Fluorodeoxyglucose
• Synaptic activity

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Cholinergic Ligands in AD
Kuhl et al, Neurology 1999
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Markers of Alzheimers Disease Temporal-Parietal
Hypometabolism
C
AD1
AD2
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Posterior Cingulate Hypometabolism
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FDG PET and AD Diagnosis

• Hoffman et al., J Nucl Med 2000 (N22)
• Pathologically confirmed AD
• sensitivity 90, specificity 65
• Silverman et al., JAMA 2001
• Progressive dementia (N146)
• sensitivity 93, specificity 76
• Pathologically confirmed AD (N138)
• sensitivity 94, specificity 73

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FDG-PET Predicts Decline

• Baseline PET predicts MMSE change in AD patients
  (Jagust et al., 1996)
• Baseline PET predicts decline from
  memory-impairment to dementia (Minoshima et al,
  1997)
• Baseline PET predicts memory decline in
  nondemented ApoE4 carriers (Small et al, 2000)
• Baseline PET predicts decline from normal to MCI
  (DeLeon et al., 2001)

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PET Metabolic Rates Predict Rate of Decline in AD
MMSE Change
r0.58
Post Temp Ctx rCMRglc (mg/100g/min)
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Regional Glucose Metabolism is Correlated with
Cognitive Function
Delayed Recall
Delayed Recall
left temporal lobe
left hippocampus
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2-year Glucose Metabolic Decline in Asymptomatic
ApoE 4 Heterozygotes
P lt 0.001
Reiman et al., PNAS 2001
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(No Transcript)
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Asymptomatic Subjects Per Treatment Group to
Detect a Drug Effect in Two YearsPost Cingulate
rCMRglc, 80 Power, p 0.01, two tailed
Number of Subjects
Reiman et al, PNAS 2001
Estimated Drug Treatment Effect
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AD Patients per Treatment Group to Detect a Drug
Effect in 1 yearFrontal rCMRglc, 80 Power, p
0.01, two tailed
Number of Subjects
Estimated Drug Treatment Effect
Reiman et al
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FDG-PET as a Surrogate PositivesLink between
PET and clinical decline

• PET predicts clinical decline
• Biologically plausible on the pathway for AD
• sensitive and specific for pathology
• related to pathology, synaptic function
• correlated with cognition
• Statistically powerful

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FDG-PET as a Surrogate NegativesLink Between
PET and Disease Modification

• Problem
• Inability to distinguish symptomatic from
  disease-modifying drug effects
• Solutions
• Randomized start or withdrawal design
• Use PET tracers that reflect basic biology of AD
  amyloid imaging agents
• Assess PET in symptomatic drug treatments

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Technical Considerations

• Standardization of multisite acquisition
• state
• input function
• attenuation correction
• resolution
• Standardization of data analysis
• quantitation metabolic rates, ratios
• regions-of-interest, atlas and voxel-based

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Summary

• FDG PET shows potential as a surrogate but
  clearly has not been confirmed
• Very sensitive in detecting decline, and
  statistically powerful
• Strong links with clinical symptoms and
  pathology, questions on disease modification
• Incorporation of PET in clinical trials will help
  address questions